Objective: Physical activity is inversely associated with depression in adolescents but the overall associations are fairly weak, suggesting individual differences in the strength of the associations. The aim of this study was to investigate whether plasticity genes modify the reciprocal prospective associations between physical activity and depressive symptoms found previously. Methods: In a prospective population-based study (N=1196), physical activity and depressive symptoms were assessed three times, around the ages of 11, 13.5 and 16. Structural Equation Modeling was used to examine reciprocal effects of physical activity and depressive symptoms over time. The plasticity genes examined were 5-HTTLPR, DRD2, DRD4, MAOA, TPH1, 5-HTR2A, COMT, and BDNF. A cumulative gene plasticity index consisting of three groups (low, intermediate and high) according to the number of plasticity alleles carried by the adolescents was created. Using a multi-group approach we examined if the associations between physical activity and depressive symptoms differed between the three cumulative plasticity groups as well as between the individual polymorphisms. Results: We found significant cross-sectional and cross-lagged paths from physical activity to depressive symptoms and vice versa. Neither the cumulative plasticity index nor the individual polymorphisms modified the strengths of these associations. Conclusion: Associations between adolescents’ physical activity and depressive symptoms are not modified by plasticity genes.